This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Colorectal cancer is the fourth leading cause of cancer-related deaths worldwide. This relatively poor survival results, in part, due to genetic changes during the development of colorectal cancer that reduce the ability of tumor cells to undergo apoptosis (programmed cell death) and cause resistance to chemotherapy. Recent evidence has demonstrated that the Raf kinase inhibitory protein (RKIP) is an effector of chemotherapy-triggered apoptosis and metastasis suppressor in human cancers. As opposed to RKIP, signal-transducer-and-activator-of-transcription-3 (STAT3) is an oncogene that inhibits apoptosis and promotes tumor formation and metastasis in human colon cancer. Inhibitors of STAT3 have been proposed for colon cancer therapy. We have taken two approaches to determine if RKIP protein level is predictive of colon cancer patient survival and if RKIP can inhibit STAT3-triggered colon cancer metastasis. In the first, we are analyzing the expression of RKIP and STAT3 in 160 biopsied colon cancer tumor tissues. We will correlate the expression of RKIP and STAT3 with patient survival over a 5 year period. In our second approach, we have genetically created 7 human colon cancer cell lines to determine if the expression of RKIP can block STAT3 triggered metastasis. These cell lines will differ in the expression of STAT3 and RKIP (high vs none) with various combinations. We are now prepared to inoculate the 7 cell lines into mice and monitor the movement of the colon tumor cells to distal organs (i.e., lung, liver). Our hypothesis is that RKIP will block STAT3-triggered metastasis.